Disorders of Immune Response

Innate specificity

non-specific, first response time immediately from birth, second time is same as first, phagocytes (neutrophils, macrophages, etc), plasma components inflammation mediators (cytokines, PGs, histamine, etc)

Adaptive specificity

very specific, first response is delayed (needs to be “primed”), second response is immediate/robust, cellular components are lymphocytes (t & B), antibodies act as plasma components

Humoral immunity

mediated by B lymphocytes which stimulate production of antibodies that target pathogens and toxins

Cell-mediated immunity (CMI)

mediated by T lymphocytes (t cells), which destroy infected or abnormal cells and coordinate immune responses

Antigens

substance that triggers an immune response in the body - self & non-self

Self antigens

HLA proteins label cells of the individual and the immune system ignores self-antigens

Non-self

immune system recognizes specific non-self antigens as foreign and develop a specific response to that particular antigen (memory cells produce quick response)

Antibodies (immunoglobulins)

produced by plasma cells to identify and neutralize foreign antigens

Antibodies bind to antigens to initiate:

neutralization, opsonization, and complement activation

Neutralization

directly block the antigen

Opsonization

mark the pathogen (antigen) for removal by macrophages

Complement Activation

antibodies bind to proteins of the complement system, activating MAC which helps to destroy foreign cells by punching holes in their membranes

IgG

most common in blood, produced during the secondary immune response when the body exposed to an antigen for the second time

IgM

first to increase, produced during the primary immune response after initial exposure to an antigen

IgA

common in secretions (tears, saliva, breast milk)

IgE

responsible for allergic response and parasitic infections

IgD

helps activate B cells

Human leukocyte antigen (HLA)

sets of molecules displayed on cell surfaces and each person has a unique MHC (major histocompatibility complex)

MHC controls…

the immune response through recognition of “self” and “non-self”; responsible for antigen presentation and lymphocyte recognition

MHC type 1

receptors recognized by CD8 (T-cytotoxic)

MHC type 2

receptors recognized CD4 (t-helper)

Graft

a cell, tissue, or organ transplanted to replace damaged tissue and is categorized based on the genetic relationship between the donor and recipient

Allogeneic (allograft)

the donor and recipient are related or unrelated but share similar HLA types

Syngeneic (synegeic graft)

the donor and recipient are identical twins

Autologous (autograft)

the donor and recipient are the same person

Many primary immunodeficiency disorders traced to…

deficiency in stem cells that can be cured with allogeneic stem cell transplantation from an unaffected donor

Example of SCT

SCIDs, Wiskott-Aldrich syndrome

For stem cell transplantation to be effective…

bone marrow cells of the host are destroyed by myeloablative doses of chemotherapy and cells can repopulate the bone marrow and reestablish hematopoiesis

Transplant rejection

a condition when the recipient’s immune system attacks a transplanted organ or tissue due to differences in their genetic markers (HLA)

Hyperacute rejection

antibody-mediated immune response that occurs almost immediately (minutes or hours) after transplantation (type 3 hypersensitivity reaction)

Acute rejection

occurs within first few months after transplantation with signs of organ failure (could occur months or years after immunosuppression has been terminated)

cell mediated - t cells response to antigens in the graft tissue

Chronic rejection

occurs after prolonged period, results from immune mediated inflammatory graft injury (mechanism is unclear)

manifested with dense fibrosis of the transplanted organ

progressive decline in organ function

Graft-versus-host disease

occurs after allogenic transplants when graft (transplant) cells recognize patients antigens as foreign

donor t-cells recognize and attack HLA on host cells

GVHD common after allogeneic bone marrow transplants

Requirements for GVHD

• transplant must have a functional cellular immune component

• recipient’s tissues must bear antigens foreign to the donor cells

• recipient’s immunity must be compromised to the point that it cannot destroy donor cells

Acute GVHD

within 100 days of transplantation - skin, rushes, GI symptoms

Chronic GVHD

after 100 days - affects multiple organ systems

Transplant rejections

occurs when the recipient’s immune system attacks the transplanted organ (e.g. kidney, heart)

Hyperacute rejection timeframe

minutes or hours

Acute transplant rejection time frame

several months

Chronic transplant rejection time frame

several years

Type 1 - immediate hypersensitivity (allergic reaction)

rapid immune reaction that occurs within minutes of re-exposure to a specific antigen

Common types of type 1 hypersensitivity

skin rashes, hay fever

Causative mechanisms of type 1 hypersensitivity

exposure to allergen, development of IgEs, degranulation of mast cells

Atopic reactions

localized to a particular tissue or organ

Hay fever

allergic rhinitis - nasal mucosa

Atopic dermatitis/eczema

skin (urticaria)

Asmtha

bronchial mucosa

Allergic conjuctivitis

eye

Systemic reactions of type 1 hypersensitivity

involve multiple organs or the entire body - anaphylaxis

First exposure to allergen

IgEs form and bind to mast cells and become sensitized

Second expsoure

mast cells release histamine that causes vasodilation, increased vascular permeability, edema

Initial phase of type 1 hypersensitivity

occurs within minutes of allergen exposure

release of mediators such as histamine causes vasodilation, vascular leakage, smooth muscle contraction

Late phase of type 1 hypersensitivity

begins about 2-8 hours after exposure

intense infiltration of tissues with eosinophils, lymphocytes, and basophils

cytokines and other inflammatory mediators cause persistent tissue inflammation and injury

Anaphylaxis

severe, life-threatening systemic type 1 hypersensitivity reaction caused by a widespread response to inflammatory mediators

• histamine, kinins, and PGs cause systemic vasodilation

• acetylcholine, kinins, leukotrienes can cause bronchoconstriction

What will happen with arterioles vasodilate throughout the body?

severe hypoxia

What will happen when the bronchioles contrict?

airway obstruction

Manifestations of anaphylaxis - skin

generalized itching or tingling, flushing, urticaria

Manifestations of anaphylaxis - respiratory

wheezing, bronchospasm, difficulty breathing

Manifestations of anaphylaxis - cardiovascular

hypotension, tachycardia, dizziness

Manifestations of anaphylaxis - GI

abdominal cramps, nausea, vomiting, and diarrhea

Manifestations of anaphylaxis - neurological

anxiety, confusion, dizziness, or fainting

Manifestations of anaphylaxis - edema

around the eyes, lips, tongue, hands, and feet

Anaphylaxis treatment

requires first aid response (EpiPen & call 911)

treatment in ED - epinephrine, glucocorticoids, antihistamines, oxygen, stabilize BP

Type 2 Cytotoxic hypersensitivity

antigen is usually present on cell membrane, may be normal body component or exogenous

circulating IgMs and IgGs react with antigens of the surface of the cells triggering destruction by phagocytosis or cytolytic enzymes

Examples of Type 2 reactions

Response to incompatible blood transfusion

Hemolytic disease of the newborn

Type 2 Pathogenesis

• antibodies bind to surface antigens activate complement system proteins that cause cell lysis

• antibodies on the cell surface act as a “tag” immune cells recognize the antibody’s Fc portion, release toxic substances and induce apoptosis in the targeted cell

Type 2 hypersensitivity disorders

myasthenia gravis - antibodies attach acetylcholine receptors

graves’ disease - antibodies attack TSH receptors

Type 3 immune complex hypersensitivity

mediated by the formation of insoluble antigen-antibody complexes that activate the complement pathway

How Type 3 immune complex hypersensitivity works

• antigen binds to antibodies to form immune complexes

• antigen-antibody complexes deposit in tissues or the lining of blood vessels

  • immune complexes activates the complement pathway, which triggers an inflammatory response

• responsible for the vasculitis seen in certain autoimmune diseases

Type IV hypersensitivity

delayed hypersensitivity reaction mediated by T lymphocytes - first and second exposure

First exposure type 4 hypersensitivity

antigen is presented to T-cells; sensitized T-cells are formed

Second exposure type 4 hypersensitivity

t-cells release cytokines-activate cytotoxic T (CD8) like tuberculin test, contact dermatitis

Autoimmune disorders

result of loss of self tolerance when the immune system produces antibodies against own cells or tissues

what normally happens (autoimmune disorders)

self-reactive immune cells are eliminated in the lymphoid organs or kept under control by regulatory T cells

If self-tolerance is lost (autoimmune disorders)

self-reactive immune cells escape these controls and may produce autoantibodies against the body’s own antigens

Predisposing factors of autoimmune disorders

familial/genetic factors - certain HLA types are linked autoimmune disease

sex-differences: many occur more frequently in women than men

Systemic autoimmune disorders

SLE, rheumatic fever, rheumatoid arthritis, polyarteritis nodosa

Multiple sclerosis

central nervous system

Hashimoto’s thyroiditis & Graves’ disease

thyroid

SLE Immune complexes form…

and deposit in tissues, triggering inflammation and tissue necrosis

vasculitis develop in many organs (impair blood supply to tissues)

Autoimmune hemolytic anemia

blood

Myasthenia gravis

muscle

Manifestations vary depending on the organ involvement but common include:

characteristic facial rash (butterfly rash), arthralgia (pain in joints), cardiovascular problems

SLE lab tests

Serum antibodies, LE cells

SLE treatment

glucocorticoid, nonsteroidal anti-inflammatory drugs

Evaluate criteria for an autoimmune disorder

• confirm evidence of an autoimmune response through appropriate immunologic findings

• exclude other conditions that could explain or cause the immune response

• no other identifiable cause should account for the disorder

Immunodeficiency

partial or complete loss of one or more components of the immune system, resulting in an increased risk of infections and cancer

Primary immunodeficiencies

group of disorders caused by genetic or inherited defects in one or more components of the immune system

Secondary or acquired immunodeficiencies

loss of immune response from specific causes - infections, splenectomy, malnutrition, immunosuppressant drugs, radiation, chemotherapy

Acquired Immunodeficiency Syndrome (AIDS)

chronic infectious disease caused by the human immunodeficiency virus (HIV)

HIV destroyes…

helper T cells (CD4 lymph) which causes gradual loss of immune response

Increased susceptibility to secondary infections and cancer -

opportunistic diseases

AIDS other characteristics

• prolonged latent period

• development may be suppressed by antivirals

HIV-positive individual

virus is known to be in the body - no evidence of immunosuppression

AIDS is marked by

clinical symptoms and multiple complications

individual often identified as HIV-positive before development of AIDS

HIV caused by…

retrovirus - contains reverse transcriptase

HIV - 1

major cause of AIDS in US and Europe

HIV - 2

major cause of AIDs in central Africa

Transmission of HIV

through body fluids like blood, semen, vaginal fluids

Which of the body cells have CD 4 proteins and CD4 receptors?

T-helper cells